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Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function
BACKGROUND AND AIMS: Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9(+) hepatocytes in response to the acute liver injury and repair are poorly understood. METH...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468867/ https://www.ncbi.nlm.nih.gov/pubmed/37649095 http://dx.doi.org/10.1186/s13578-023-01104-5 |
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author | Qin, Dan Wang, Rui Ji, Jinwei Wang, Duo Lu, Yuanyuan Cao, Shiyao Chen, Yaqing Wang, Liqiang Chen, Xiangmei Zhang, Lisheng |
author_facet | Qin, Dan Wang, Rui Ji, Jinwei Wang, Duo Lu, Yuanyuan Cao, Shiyao Chen, Yaqing Wang, Liqiang Chen, Xiangmei Zhang, Lisheng |
author_sort | Qin, Dan |
collection | PubMed |
description | BACKGROUND AND AIMS: Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9(+) hepatocytes in response to the acute liver injury and repair are poorly understood. METHODS: In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl(4) and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H(2)O(2)) in order to induce cellular damage in an in vitro setting. RESULTS: We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H(2)O(2)-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. CONCLUSIONS: Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01104-5. |
format | Online Article Text |
id | pubmed-10468867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-104688672023-09-01 Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function Qin, Dan Wang, Rui Ji, Jinwei Wang, Duo Lu, Yuanyuan Cao, Shiyao Chen, Yaqing Wang, Liqiang Chen, Xiangmei Zhang, Lisheng Cell Biosci Research BACKGROUND AND AIMS: Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9(+) hepatocytes in response to the acute liver injury and repair are poorly understood. METHODS: In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl(4) and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H(2)O(2)) in order to induce cellular damage in an in vitro setting. RESULTS: We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H(2)O(2)-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. CONCLUSIONS: Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01104-5. BioMed Central 2023-08-30 /pmc/articles/PMC10468867/ /pubmed/37649095 http://dx.doi.org/10.1186/s13578-023-01104-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Qin, Dan Wang, Rui Ji, Jinwei Wang, Duo Lu, Yuanyuan Cao, Shiyao Chen, Yaqing Wang, Liqiang Chen, Xiangmei Zhang, Lisheng Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function |
title | Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function |
title_full | Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function |
title_fullStr | Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function |
title_full_unstemmed | Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function |
title_short | Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function |
title_sort | hepatocyte-specific sox9 knockout ameliorates acute liver injury by suppressing shp signaling and improving mitochondrial function |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468867/ https://www.ncbi.nlm.nih.gov/pubmed/37649095 http://dx.doi.org/10.1186/s13578-023-01104-5 |
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